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Target Dose vs Highest Tolerated Dose: Beta-

Blocker Therapy in Heart Failure in the Elderly

JASMINE PETERSON, PHARMD

PGY-2 AMBULATORY-CARE RESIDENT

COMMUNITYCARE CLINIC

UNIVERSITY OF TEXAS COLLEGE OF PHARMACY AT AUSTIN

OCTOBER 7, 2016

OBJECTIVES

By the end of this presentation attendees will be able to:

Understand the epidemiology and pathophysiology of heart failure

Describe the challenges of managing heart failure in elderly patients

Summarize the literature regarding the controversy behind achieving target doses

of beta blockers in elderly heart failure patients

2

DEFINITION OF ELDERLY

According to the World Health Organization (WHO), most developed countries

have accepted the chronological age of ≥65 years as a definition of “elderly” or older

persons

A consensus definition does not exist

May vary in underdeveloped countries

3

http://www.who.int/healthinfo/survey/ageingdefnolder/en/

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HEART FAILURE BACKGROUND

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HEART FAILUREHeart failure (HF) is defined as a complex clinical syndrome caused by structural or

functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood

5

Figure 1.

DEFINITIONS

HF reduced ejection fraction (HFrEF)

Systolic dysfunction

Secondary to dilated ventricles

Left ventricular ejection fraction (LVEF) ≤40%

Randomized controlled trials have mainly enrolled these patients

HF preserved ejection fraction (HFpEF)

Diastolic dysfunction

Secondary to impaired ventricular filling

LVEF ≥50%

Currently, efficacious therapies have not shown proven mortality benefit

Circulation. 2013;128:e240-e327

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CLASSIFICATIONS Table 1.

ACCF/AHA NYHA

A At high risk for HF but without

structural heart disease or symptoms

of HF

None

B Structural heart disease but without

signs and symptoms of HF

I No limitation on physical activity

C Structural heart disease but with

prior or current symptoms of HF

I No limitation on physical activity

II Slight limitation of physical activity

III Marked limitation of physical activity

IV Unable to carry on any physical activity

without symptoms of HF

D Refractory HF requiring specialized

interventions

IV Unable to carry on any physical activity

without symptoms of HF

Circulation. 2013;128:e240-e327

American Heart Association (AHA); American College of Cardiology Foundation (ACCF) ; New York Heart Association(NYHA)

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EPIDEMIOLOGY

• Lifetime risk of developing HF is 20% for patients ≥40yo

• >650,000 new HF cases each year

Prevalence

• 50% within 5 years of diagnosis

Mortality

• 75% occur in patients >65yo

• Leading cause of readmissions

• >$30 billion for HF care annually

Hospitalizations

Circulation. 2013;128:e240-e327

Christine K. Cassel et. al., ed. 2003. Geriatric Medicine: An Evidence Based Approach - 4th Ed

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PREVALENCE OF HF IN THE ELDERLY

0

2

4

6

8

10

12

14

16

20-39 40-59 60-79 80+

Perc

enta

ge

Age (years)

Figure 2. Prevalence of HF by sex and age

(National Health and Nutrition Examination Survey 2009-2012)

Male

Female

Factors contributing to the rise and

incidence of HF

Age-related cardiovascular changes

High prevalence of cardiovascular

disease

Improved therapies for coronary

heart disease

9Darish Mozaffarian et al. Circulation.2016;133:e133:e38-e360.

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PATHOPHYSIOLOGY

Natriuretic Peptide system (NPS)

Sympathetic Nervous System (SNS)

Renin Angiotensin Aldosterone System (RAAS)

ClinTher. 2015;37:2199–2205

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Figure 3.

Myocardial Injury RAAS

SNS

NPS

Vasoconstriction

↑Norepinephrine, adrenaline, BP, HR, contractility, etc.

Vasoconstriction

↑BP, sympathetic tone, aldosterone, hypertrophy, fibrosis, etc.

Vasodilation

↓BP, hypertrophy, fibrosis, sympathetic tone, etc.

CLINICAL PRESENTATION/RISK FACTORS

Primary Symptoms

• Dyspnea

• Fatigue

• Edema

• Exercise intolerance

Risk Factors

• Coronary artery disease (CAD)

• Valvular heart disease

• Uncontrolled chronic disease (i.e. Hypertension)

• Cardiomyopathy

• Myocarditis

• Pericardial disease

Circulation. 2013;128:e240-e32711

Am J Geriatr Pharmacother. 2009;7:233–249.

CHALLENGES OF MANAGING HF IN THE ELDERLY

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• Influence drug pharmacokinetics and dynamics

Physiological age-related changes

• Higher risk for drug-related side effects

• Polypharmacy

More complex comorbidities

• Limited access to caregivers and specialists

• Cognitive impairment

• Financial problems affect therapy adherence

Social issues

Am J Geriatr Pharmacother. 2009;7:233–249.

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TREATMENT: NON-PHARMACOLOGIC AND

PHARMACOLOGIC2013 ACCF/AHA GUIDELINE FOR THE MANAGEMENT OF HF

2016 ACC/AHA/HFSA FOCUSED UPDATE ON NEW PHARMACOLOGICAL THERAPY FOR HF: AN UPDATE OF THE 2013

ACCF/AHA GUIDELINE

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NON-PHARMACOLOGIC RECOMMENDATIONS

Patient education

Restrict sodium intake (1.5- 2 grams/day)

Weight control

Manage/control underlying causes

Intensive follow-up

Smoking cessation

Restrict alcohol

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Am J Geriatr Pharmacother. 2009;7:233–249

PHARMACOLOGIC RECOMMENDATIONS Table 3.

Stage Goals Treatment Recommendations

Stage A Prevent structural heart damage and

promote heart healthy lifestyle

ACEI/ARB in patients with vascular

disease or DM

Stage B Prevent HF symptoms and further cardiac

remodeling

ACEI/ARB and beta blockers as

appropriate

Stage C Control symptoms, prevent morbidity and

mortality, and slow progression of worsening

cardiac function

Diuretics, ACEI/ARB, ARNI, beta

blockers, aldosterone antagonists,

hydralazine/isosorbide dinitrate, digoxin,

ivabradine

Stage D Control symptoms, improve quality of life,

reduce hospital admissions, establish end-of-

life goals

Advanced care measures, heart

transplant, chronic inotropes, implantable

cardiac device, palliative care

15Angiotensin-converting-enzyme inhibitor (ACEI), Angiotensin receptor blocker (ARB) , Angiotensin Receptor Neprilysin Inhibitor (ARNI)

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BETA BLOCKERS (BBs)BACKGROUND AND ROLE IN HF

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PROPOSED MECHANISM OF ACTION/BENEFICIAL EFFECTS

ClinTher. 2015;37:2199–2205

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Myocardial Injury

Beta Blockers

Figure 4.

ROLE OF BETA BLOCKERS IN HF

2013 ACCF/AHA HF guidelines states:

“Use of 1 of the 3 beta blockers proven to reduce mortality (i.e. bisoprolol, carvedilol, and

sustained-release metoprolol succinate) is recommended for all patients with current or

prior symptoms of HFrEF, unless contraindicated, to reduce morbidity and mortality.”

Class I, Level of evidence A

“Clinicians should make every effort to achieve the target doses of the beta blockers

shown to be effective in major clinical trials.”

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EVIDENCE SUPPORTING BETA BLOCKER RECOMMENDATIONS

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Table 4. Major Placebo- Controlled Trials of BBs Supporting HF Guideline Recommendations

Drug Trial Mean

follow-up

(mo)

N Patient

Population

Mean

age

(yo)

Target

dose

% Achieved

Target dose

Mortality/

Morbidity

(RRR)

Metoprolol

XL

MERIT-HF

(1999)

12 3991 NYHA ll-lV;

LVEF <40%

64 200 mg daily 64% ↓ 34%/ ↓ 18%

Bisoprolol* CIBIS-II

(1999)

15.6 2647 NYHA class III-

IV; LVEF <35%

61 10 mg daily 48% ↓ 34%/ ↓ 20%

Carvedilol COPERNICUS

(2002)

10.4 2289 NYHA class lV;

LVEF <25%

63 25 mg BID 65% ↓ 35%/ ↓ 20%

CIBIS-II (Cardiac Insufficiency Bisoprolol Study II), MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure), COPERICUS (Carvedilol Prospective Randomized Cumulative Survival)

* Not approved in the US

RRR= Relative Risk Reduction

BACKGROUND: BETA BLOCKERS IN THE ELDERLY

20

Am J Cardiol 2005;95:896–898

RESULTS

Elderly Non-Elderly

21Am J Cardiol 2005;95:896–898

Figure 5.

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BETA BLOCKER CLINICAL TRIALS INVESTIGATED

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Table 5. BB Clinical Trials Included in Meta-analysis

BB Trial Mean

follow-up

(mo)

N Patient

Population

Mean age

(yo)

Inclusion

Criteria

(Age, yo)

% ≥70yo Mortality/

Morbidity

(RRR)

Metoprolol XL MERIT-HF (1999) 12 3991 NYHA ll-lV;

LVEF <40%

64 40-80 31% ↓ 34%/ ↓ 18%

Bisoprolol* CIBIS-II

(1999)

15.6 2647 NYHA class III-

IV; LVEF <35%

61 18-80 20% ↓ 34%/ ↓ 20%

Carvedilol COPERNICUS

(2002)

10.4 2289 NYHA class lV;

LVEF <25%

63 ≥18 NR ↓ 35%/ ↓ 20%

Carvedilol Carvedilol U.S. Trials

(1996)

6.5 1094 NYHA ll-lV;

LVEF <35%

59 ≥18 NR ↓ 65%/ ↓ 27%

Bucindolol* BEST (2001) 24 2708 NYHA llI-lV;

LVEF <35%

60 >18 28% NS/ ↓ 8%

* Not approved in the US ,NS= not significant ;NR= Not reported, BEST (Beta-Blocker Evaluation of Survival Trial)

Am J Cardiol 2005;95:896–898

Is achieving target doses of beta blockers in elderly HF patients

associated with better clinical outcomes?

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Highest tolerated dose Target dose

CLINICAL QUESTION

EVIDENCE EVALUATING THE EFFECT OF BETA

BLOCKERS ON CLINICAL OUTCOMES IN

ELDERLY HF PATIENTS

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THE EFFECTS OF BETA-BLOCKERS ON MORBIDITY AND

MORTALITY IN A POPULATION-BASED COHORT OF 11,942

ELDERLY PATIENTS WITH HEART FAILURE

SIN D., MCALISTER F., ET AL. AM J MED. 2002;113:650–656

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SIN 2002

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Aim

Evaluate the associations between BBs and outcomes in older HF patients

Design

Retrospective cohort study

Inclusion Criteria

All residents of Alberta, Canada ≥ 65yo who had at least 1 hospitalization for HF

between 1994 and 1999

SIN 2002

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Exclusion Criteria

Patients who died during the index hospitalization

Patients who had been hospitalized for HF 2 years before the index hospitalization

Endpoints

All-cause mortality

HF hospitalizations

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SIN 2002

Methods

Patients followed from the date of index hospitalization until the date of death, first

re-hospitalization for HF, or December 31, 1999, whichever came first

Evaluated 11,942 patients

Divided daily dose of BBs into 3 categories:

Not dispensed

Lower dose (<50% of target dose)

Higher dose (≥50% of target dose)

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SIN 2002: RESULTS

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Male (~50%)

+80yo (58%)

2569 (22%) had Charlson comorbidity scores of ≥ 2

Of 11,942 patients, 1162 (10%) received BB therapy

519 (45%) received lower doses

643 (55%) received higher doses

Most frequently prescribed BB was metoprolol (42%)

Median follow-up was 21 months

SIN 2002: RESULTS

Table 4. Associations between use of Beta Blockers, by dose, with All-Cause

Mortality or Hospitalization for HF

Total Cohort (n = 11,942)

Drug All-Cause Mortality HF Hospitalizations

Beta Blocker 0.72 (0.65-0.80); 28% RRR 0.82 (0.74-0.92); 18% RRR

Lower Dose 0.77 (0.67-0.88) 0.92 (0.80- 1.07)

Higher Dose 0.64 (0.55-0.75) 0.71 (0.60-0.83)

RRR= relative risk reduction

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SIN 2002: AUTHOR’S CONCLUSIONS

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Benefits of BBs seen in randomized trials extend to elderly HF patients

28% reduction in mortality and 18% reduction in hospitalizations were consistent

with data from previous trials

All doses of BBs were associated with benefit

Greater benefit seen in patients receiving higher doses

Randomized controlled trials comparing BB doses to functional and clinical outcomes

is warranted

SIN 2002: CRITIQUE

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• Large sample size

• Baseline characteristics similar between groups

• Evaluated BB dose associations with mortality and morbidity

Strengths

• Retrospective study

• Unable to monitor adherence

• Unable to capture patients without insurance

• Did not collect data on functional status/severity of HF

• Did not determine if patients had systolic or diastolic dysfunction

• Included BBs not proven to reduce morbidity and mortality in HF

• Did not report number of clinical events associated with each dosing group

Limitations

DOES THE TARGET DOSE OF NEUROHORMONAL

BLOCKADE MATTER FOR OUTCOME IN

SYSTOLIC HEART FAILURE IN OCTOGENARIANS?

BARYWANI S., ET AL. INTL J CARDIOLOGY 2015. 187:666-672.

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BARYWANI 2015 Aim

Investigate whether patients receiving ≥50% target dose outperform those

receiving <50% target dose, despite maximum up-titration, and whether the target

dose outperforms ≥50% or <50% target dose groups, in an elderly HF population

Design

Retrospective cohort study

2 specialized HF clinics in Gothenburg, Sweden

Inclusion Criteria ≥ 80yo LVEF ≤40%

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BARYWANI 2015

Exclusion Criteria LVEF >40%

Endpoints Primary:

All-cause mortality

Secondary: Cardiac mortality Hospitalization due to worsening HF

35

BARYWANI 2015

Methods Up-titrated to target dose or highest tolerated dose over 3-6 month period by

HF-specialized nurse and cardiologist Based on clinical assessment and vital signs ( i.e. HR <55, SBP <100mmHg)

Definitions of groups: Low dose: <50% of the target dose Intermediate: ≥ 50% of target dose but less than the target dose Highest dose: target dose

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BARYWANI 2015: RESULTS

185 patients evaluated

50% received low dose

29% received intermediate dose

21% received high dose

Most frequently prescribed BB was metoprolol succinate (84%)

More patients with underlying CAD and HTN were in intermediate and high dose

BB groups (P= 0.009 and 0.004, respectively)

No significant differences in HF hospitalizations or non-cardiac deaths

No significant differences in HR between all 3 groups after up-titration

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BARYWANI 2015 : RESULTS

All-cause mortality

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Figure 5.

BARYWANI 2015 : RESULTS

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Cardiac mortality Figure 6.

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BARYWANI 2015

Safety

Main reasons for not reaching target doses

Symptomatic bradycardia (53%)

Symptomatic hypotension (46%)

Worsening pulmonary symptoms (1%)

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BARYWANI 2015: AUTHOR’S CONCLUSIONS

Clinical outcome of BB therapy is independent of BB dose when the target HR is

achieved

Randomized controlled trials are needed to confirm results

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BARYWANI, ET AL . 2015 : CRITIQUE

• Evaluated elderly patients with multiple comorbidities

• Evaluated optimal clinical outcomes

• Optimally titrated medications at HF clinic

• Used guideline recommended BBs

Strengths:

• Small sample size

• Retrospective study

• Differences in baseline characteristics

Limitations:

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RELATIONSHIP BETWEEN DIFFERENT DOSES OF BETA-

BLOCKERS AND PROGNOSIS IN

ELDERLY PATIENTS WITH REDUCED EJECTION FRACTION

PELAEZ J., ET AL. INTL J CARDIOLOGY 2016.220: 219–225.

43

PELAEZ 2016

Aim

To determine the impact of different doses of BBs on survival and admission for

HF in elderly patients with reduced ejection fraction (REF)

Design

Single-center observational study

Madrid, Spain

Inclusion Criteria Age ≥ 75yo LVEF ≤ 35%

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PELAEZ 2016

Exclusion Criteria

Patients who died or suffered a major cardiovascular event (HF admission

requiring intravenous diuretics or sustained ventricular arrhythmia)

Endpoints Primary:

Time to all-cause death

Secondary:

Time to first HF admission requiring intravenous diuretics

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PELAEZ 2016

Methods

784 patients assessed for eligibility

Maximal tolerated doses of carvedilol, bisoprolol, metoprolol succinate, and nebivolol were recorded

Six months after diagnosis, patients were divided into 3 groups depending on BB dose:

No BB (NBB)

Low dose (LD): <50% of target dose

High dose (HD): ≥50% of target dose

46

PELAEZ 2016: RESULTS

559 patients included

Median age ~80yo

Significant differences baseline characteristics in regards to age, QRS complex width, resting HR, COPD, cognitive impairment, functional disability, ischemic etiology of REF, NYHA class, in the use of implantable cardioverter defibrillator (ICD), and ivabradine

24% received NBB

46% received LD

30% received HD

Bisoprolol (59%) was the most prescribed BB

Median follow-up was ~30 months47

PELAEZ 2016: RESULTS

48

Figure 7.

years years

Cum

ula

tive

Pro

bab

ility

Cum

ula

tive

Pro

bab

ility

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PELAEZ 2016: AUTHOR’S CONCLUSION

BB therapy is associated with a significant reduction in mortality among elderly

patients with REF, regardless of dose

BB therapy may not be associated with a decrease in HF admissions in this patient

population

Further studies needed to determine optimal doses and their association with

clinical outcomes

49

PELAEZ, ET AL. 2016: CRITIQUE

• Appropriate statistics

• Patient population was a reflection of real-world clinical practice

• Assessed appropriate clinical outcomes

Strengths:

• Single-center observational study

• Excluded patients with serious events in the first 6 months after diagnosis

• Did not collect data on changes in BB doses during follow up

• Included BB (nebivolol) not shown to reduce mortality

• Did not evaluate safety

Limitations:

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LITERATURE SUMMARY

Sin 2002

• ≥ 65yo HF patients

• All BB doses are associated

with benefit (reduction in

morbidity and mortality)

• Greater benefit seen with

higher doses

Barywani 2015

• ≥ 80yo HFrEF patients

• Highest tolerable doses of

BB achieved similar

mortality and morbidity

outcomes to target doses

Pelaez 2016

• ≥ 75yo HFrEF patients

• All BB doses improved

survival

• Found no relationship

between BB intake and HF

hospitalizations

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CONCLUSION

Up-titration of BBs to target doses in the elderly is challenging

According to current literature:

Survival is independent of BB dose

Benefit on morbidity is inconsistent

Common reasons for up-titration failure:

Symptomatic bradycardia, symptomatic hypotension, worsening pulmonary symptoms

Randomized controlled trials are needed to determine the optimal BB doses

Would recommend to initiate BBs in this patient population at low doses and titrate up

to the highest tolerated dose based on HR and BP 52

ACKNOWLEDGEMENTS

Evaluator:

Jason Jokerst, PharmD BCPS

Committee:

April Hinds, PharmD, BCACP

Lindsay Vasquez, PharmD, BCPS, BCACP, CDE

Maaya Srinivasa, PharmD, BCACP, CDE

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QUESTIONS

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Target Dose vs Highest Tolerated Dose: Beta-

Blocker Therapy in Heart Failure in the Elderly

JASMINE PETERSON, PHARMD

PGY-2 AMBULATORY-CARE RESIDENT

COMMUNITYCARE CLINIC

UNIVERSITY OF TEXAS COLLEGE OF PHARMACY AT AUSTIN

OCTOBER 7, 2016